The Role of Antenatal Factors on Neonatal Outcome
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Transcript of The Role of Antenatal Factors on Neonatal Outcome
The Role of Antenatal Factors on Neonatal Outcome
Jonathan M. Davis, MD
Vice-Chair of Pediatrics, Chief of Newborn Medicine
Floating Hospital for Children/Tufts Medical Center
Professor of Pediatrics
Tufts University School of Medicine
Boston, MA
Chair, Child Health Oversight Committee, NIH
Chair, Neonatal Advisory Committee, FDA
No relevant financial relationships to disclose
Outpatient deck, 1906
6
1999
Obesity in the US – A Major Public Health Problem
2009
1990
No Data <10% 10%–14 15%–19% 20%–24% 25%–29% ≥30%
CDC database
Obesity and Inflammation
Obesity is associated with marked inflammation and immune dysregulationAdipocytes undergo necrosis, promoting inflammation and macrophage recruitmentHigher circulating levels of TNF-α, IL-6, MCP-1, and TGF-β
Obesity in Pregnancy – Harmful to Mother and Infant
Schmatz et al, J Perinatology, 2010.
Obesity↑CRP ↑IL-6, IL-8↑TNFα↑leptin,↑adiponectin↑macrophages
Pregnancy↑CRP↑macrophages↑neutrophils↑IL-10
↑Inflammation
Disease
Maternal DisPre-eclampsiaGestational DMDysfunctional Labor
Lifetime Disease RiskHypertensionDMHyperlipidemiaMI
Neonatal DisLow ApgarsNICU admissionMacrosomiaPrematurity
Child/Adult DiseaseObesityDMMetabolic Syndrome
Obesity in Pregnancy is Associated with Increased Infections
Heslehurt et al. Obesity Reviews, 2008.
Obesity in Pregnancy
• Increased risks of antenatal, intrapartum, and neonatal complications
• 2-5 X increased risk of:• Diabetes
• Pre-eclampsia
• Induction of labor, emergency C-section
• Intrapartum & postpartum hemorrhage
• Chorioamnionitis
• Macrosomic infants, lower Apgars, NICU admissions
• Intrauterine death
Results: 1981-2005
• 219,173 pregnant women over 25 year period
• Mean maternal weight increased linearly → 139 lbs in 1981 to 161 lbs in 2005, or 22 pounds
• For 27 year old mothers only, mean weights increased 25 pounds in 25 years
Results
Medians (interquartile ranges); Kruskal-Wallis ANOVA test
Results
Major Risk Factors for Prematurity by Multivariate Analysis
• PROM
• Obesity
• Pre-existing diabetes
• Pre-eclampsia/hypertension
• Previous preterm/SGA infant
• In vitro fertilization
Obesity in Pregnancy Changes Immune Cell Populations
Cell Populations
Obese (n=15)
Lean (n=15)
p value
CD4+ (% lymphocytes)
45.8+9.4 44.3+12.7 ns
CD8+ (% lymphocytes)
16.4+5.8 23.5+7.4 <0.05
NKT cells 22.9+6.1 27.9+4.1 <0.05
B cells 21.9+6.2 13.3+5.3 <0.05
Maternal Obesity Impairs Cytokine Production
* p < 0.05
*
Interferon gamma response to stimulation
0
100
200
300
400
500
600
700
CD8+ cells CD4+ cells
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MF
U)
Lean
Obese
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TNF alpha response to stimulation
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100
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CD8+ cells CD4+ cells
geo
metr
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ean
(M
FU
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Lean
Obese
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TNFα response to stimulation
IFNγ response to stimulation
*
* *
Obese Pregnant Women Have Reduced Micronutrients
Lean (n=15) Obese (n=15)
RBC folate (ng/ml)
1606+559 1131+446*
Vitamin C (mg/dL)
1.3+0.2 0.9+0.3*
Vitamin E (ug/dL)
1720+394 1393+282*
(1,25) OH Vitamin D (ng/ml)
34.8+10.2 27.4+8*
Fat (%)
Protein (%)
Carb (%)
Kcal/g Vit A (g/kg)
Vit C (g/kg)
Vit E (g/kg)
Selenium (g/kg)
Control 8 16 45 3.2 4,600 0 86 0.165
Control+ AOX
8 16 45 3.2 23,000 5.6 260 0.5
Western 16 21 50 4.3 4,600 0 86 0.165
Western+ AOX
16 22 50 4.3 23,000 5.6 260 0.5
Diet Composition for Dams
Offspring Adiposity at 2 weeks
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Control Control+Aox Western Western+Aox
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Conclusions
• Mean maternal weights have increased significantly over time
• Obesity in pregnancy - increased inflammation, immune dysregulation, PPROM, chorioamnionitis, and prematurity
• Obesity one of multiple factors that increases the risk of prematurity
Fetal Inflammatory
Response
time
Trimester II Delivery
Intrauterine
infection
Preterm
birth
Brain/Lung damage
Bacterial Infection within the Uterus
Markers of Preterm Delivery
Cervix / Vagina Amniotic Fluid Serum
Bacterial vaginosis WBC CRP
G-CSF G-CSF G-CSF
TNF- TNF- TNF-
IL-1 Glucose IL-6
IL-6 IL-6
IL-8 Bacteria
FFN
RISK FACTORS: INTRAPARTUM
• Fever
• Urinary tract infection
• Premature rupture of membranes
• Chorioamnionitis/funicitis (many organisms, e.g. ureaplasma)
• Low Apgars, encephalopathy, seizures, poor neonatal outcome
Adj OR : 3.8 (0.97-15)
Fever
No Fever
Cognitive Development
Infection in the Placenta and Neonatal Brain Injury
• Bacteria present >80% by PCR, no correlation with chorioamnionits/preterm labor
• Fetal inflammation needed for brain injury
• Role of endotoxin (LPS injections in rabbits), oxidative stress (deficiency of antioxidants), cytokines (CSF) in white matter injury
• Sensitizes fetal brain to hypoxia
• May have brain anomalies at birth
• In utero insult may continue post-partum
FIR: Role for White Cell Activation
Dammann O, et al. 2001
Pathogenetic Mechanisms in PVL
Maternal infection/ Prematurity Fetal inflammation
Cytokines Ischaemia/ Microglia reperfusion
Fe++ IVH Glutamate Antioxidants
Reactive oxygen species Reactive nitrogen species
Oligodendroglial death
Slide Courtesy of Alan Leviton
PVL on MRIincreased signal intensity in white matter,
volume loss in grey matter
Growth Factorsand Hormones
Long-term Disability
ChemokinesCytokines
AdhesionMolecules
?
PrenatalInfection
Inflammatory Response
White Matter Damage
Lung Injury
Other poor outcomes
Future Research• Molecular Epidemiology
Genetic polymorphisms Genetic susceptibility
• Directed TherapiesProtectors (antenatal steroids)Anti-inflammatory agents (IL-10, CC10, ibuprofen)Antioxidants (rhSOD)
• Maternal and Neonatal Conditions Chorioamnionitis/funicitis (new FHR monitors)BPD, PVL, ROP, NEC (salivary gene analyses)
• Laboratory Techniques (microarray, Luminex)
• Assessment Techniques (PFT, CT, MRI, EEG)
….
Neonatal Abstinence SyndromeNeonatal Abstinence Syndrome
• Opioid exposure in pregnancy - 5.6 infants/1,000 births
• Incidence has tripled in the past decade• The mother may also be smoking or
taking other medications • Signs of withdrawal in 60-80% of infants
exposed to opioids
• Dysfunction of the central nervous system, gastrointestinal tract, and/or respiratory system
Neonatal Abstinence Syndrome Neonatal Abstinence Syndrome
• Prolonged treatment in hospital, high healthcare costs
• Safety and efficacy of agents not well established
• Significant variability in the incidence and severity
• Factors influencing this variability are unknown
Neonatal Abstinence Syndrome
• Genetic factors may be important
• Single nucleotide polymorphisms (SNPs): Single base pair changes that can alter protein’s function
• SNPs influence opioid dosing, metabolism, and addiction in adults
• No prior studies of genetic links to NAS
Candidate Genes for NAS
• SNPs present in 40-50% of the population have been studied in adults
• Mu Opioid Receptor (OPRM1) = Site of Action
• 118A>G SNP
• Multi-Drug Resistance Gene (ABCB1) = Transporter
• 1236C>T SNP
• 3435C>T SNP
• 2677G/T/A SNP
• Catechol-O-methyltransferase (COMT) = Modulator
• 158A>G SNP
Methods• 86 opioid exposed term infants• Mothers receiving methadone or
buprenorphine
• Infants treated with morphine or methadone
• If severe - additional medications given
• A sample of blood or saliva collected from each infant
• Incidence and severity correlated with changes in genetic profiles
Results
DEMOGRAPHICS
White 98%
Maternal Methadone 64%
Maternal Buprenorphine 36%
Maternal Smoking 78%
Maternal Benzodiazepines 12%
LOS All Infants Mean 22.3 days
LOS Treated Infants Mean 31.6 days
Treatment for NAS 65%
Treated with >2 medications 24%
OPRM1 118A>G Results
• AA vs AG/GG infants compared in models that adjust for breastfeeding and study site
• Those with the AG/GG genotype - treated less frequently and had shorter LOS
OUTCOME UNADJUSTEDRESULTS
ADJUSTED RESULTS
P-VALUE
Infant Treated
72% vs 48% OR = 0.76 (CI 0.63, 0.96)
0.006
Mean LOS 24.1 vs 17.6 days - 8.5 days 0.009
COMT 158A>G Results
• AA infants vs AG/GG infants in models that adjusted for breastfeeding and site
• AG/GG infants were treated less frequently and had shorter LOS than AA infants
OUTCOME UNADJUSTED RESULTS
ADJUSTED RESULTS
P-VALUE
Infant Treated
88% vs 60% OR = 0.79(CI 0.61, 0.99)
0.02
Mean LOS 31.1 vs 20.4 days - 10.8 days 0.005
Conclusions• NAS is a complex disorder with many
factors contributing to the incidence and severity
• SNPs in the OPRM1 and COMT genes - reduced treatment and LOS
• No associations found with ABCB1 SNPs
• Combining clinical risk factors with genetic profiling would permit personalized genetic medicine and targeted treatment regimens
Challenges in Neonatal Drug Development
• Most drugs used in newborn infants not FDA approved - safety and efficacy not established
• Small market, high liability, ethical concerns
• Significant variability in NAS treatment protocols
• Many NAS medications include alcohol or propylene glycol
• Concern for adverse long-term developmental outcomes
Future Directions
• NIH Grant – “Improving Outcomes in Neonatal Abstinence Syndrome”
• Randomize infants to receive morphine or methadone (determine best practice)
• Evaluate long-term neurodevelopmental outcomes of infants treated for NAS
• Establish other genetic factors - Addiction Array (1350 SNPs for addiction disorders)